The present invention relates to the preparation of substituted indazole of formula (I) which inhibits interleukin-1 receptor-associated kinase 4 (IRAK4).
Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammation-inhibiting substances. IRAK4 is expressed by a multitude of cells and mediates the signal transduction of Toll-like receptors (TLR), except TLR3, and receptors of the interleukin (IL)-1β family consisting of the IL-1R (receptor), IL-18R, IL-33R and IL-36R (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).
Neither IRAK4 knockout mice nor human cells from patients lacking IRAK4 react to stimulation by TLRs (except TLR3) and the IL-1β family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
The binding of the TLR ligands or the ligands of the IL-1β family to the respective receptor leads to recruitment and binding of MyD88 [Myeloid differentiation primary response gene (88)] to the receptor. As a result, MyD88 interacts with IRAK4, resulting in the formation of an active complex which interacts with and activates the kinases IRAK1 or IRAK2 (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009). As a result of this, the NF (nuclear factor)-kB signalling pathway and the MAPK (mitogen-activated protein kinase) signal pathway is activated (Wang, Deng, et al., Nature, 2001). The activation both of the NF-kB signalling pathway and of the MAPK signalling pathway leads to processes associated with different immune processes. For example, there is increased expression of various inflammatory signal molecules and enzymes such as cytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammation-associated genes, for example COX-2, IL-6, IL-8 (Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004). Furthermore, these processes may be associated with the proliferation and differentiation of particular cell types, for example monocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi, et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).
The central role of IRAK4 in the pathology of various inflammatory disorders had already been shown by direct comparison of wild-type (WT) mice with genetically modified animals having a kinase-inactivated form of IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have an improved clinical picture in the animal model of multiple sclerosis, atherosclerosis, myocardial infarction and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012). Furthermore, it was found that deletion of IRAK4 in the animal model protects against virus-induced myocarditis an improved anti-viral reaction with simultaneously reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013). It has also been shown that the expression of IRAK4 correlates with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
As well as the essential role of IRAK4 in congenital immunity, there are also hints that IRAK4 influences the differentiation of what are called the Th17 T cells, components of adaptive immunity. In the absence of IRAK4 kinase activity, fewer IL-17-producing T cells (Th17 T cells) are generated compared to WT mice. The inhibition of IRAK4 is therefore suitable for prophylaxis and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondyloarthritis, lupus erythematosus, psoriasis, vitiligo, chronic inflammatory bowel disease and viral disorders, for example HIV (human immunodeficiency virus), hepatitis virus (Staschke, et al., The Journal of Immunology, 2009; Zambrano-Zaragoza, et al., International Journal of Inflammation, 2014).
Owing to the central role of IRAK4 in the MyD88-mediated signal cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be utilized for the prophylaxis and/or treatment of disorders mediated by the receptors mentioned. TLRs and also components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, Sjögren syndrome and sepsis (Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Roger, Froidevaux, et al, PNAS, 2009; Gambuzza, Licata, et al., Journal of Neuroimmunology, 2011; Fresno, Archives Of Physiology And Biochemistry, 2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Talabot-Aye, et al., Cytokine, 2014). Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, allergic contact dermatitis, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signalling pathway (Gilliet, Conrad, et al., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali, et al., Am J Clin Dermatol, 2010; Viguier, Guigue, et al., Annals of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Dispenza, Wolpert, et al., J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab, et al., BMC Dermatology, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Wollina, Koch, et al. Indian Dermatol Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014).
Pulmonary disorders such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension also show an association with various TLR-mediated signalling pathways. The pathogenesis of the pulmonary disorders may be either infectiously mediated or non-infectiously mediated processes (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu, et al., Infection and Immunity, 2005; Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013). TLRs and also IL-1R family members are also involved in the pathogenesis of other inflammatory disorders such as Behçet's disease, gout, lupus erythematosus, adult-onset Still's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, and transplant rejection, and so inhibition of IRAK4 here is a suitable therapeutic approach (Liu-Bryan, Scott, et al., Arthritis & Rheumatism, 2005; Christensen, Shupe, et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., Immunity, 2006; Heimesaat, Fischer, et al., PLoS ONE, 2007; Kobori, Yagi, et al., J Gastroenterol, 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokine & Growth Factor Reviews, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013). Because of the mechanism of action of the compound of formula (I), they are also suitable for prophylactic and/or therapeutic use of the TLR and IL-1R family-mediated disorders endometriosis and atherosclerosis (Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Khan, Kitajima, et al., Journal of Obstetrics and Gynaecology Research, 2013; Santulli, Borghese, et al., Human Reproduction, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013).
In addition to the disorders already mentioned, IRAK4-mediated TLR processes have been described in the pathogenesis of eye disorders such as retinal ischaemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis (Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012; Guo, Gao, et al., Immunol Cell Biol, 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).
Because of the central role of IRAK4 in TLR-mediated processes, the inhibition of IRAK4 also enables the treatment and/or prevention of cardiovascular and neurological disorders, for example myocardial reperfusion damage, myocardial infarction, hypertension (Oyama, Blais, et al., Circulation, 2004; Timmers, Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sci (Lond), 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013;), and also Alzheimer's disease, stroke, craniocerebral trauma and Parkinson's disease (Brough, Tyrrell, et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, et al., The Journal of Immunology, 2011; Lim, Kou, et al., The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Noelker, Morel, et al., Sci. Rep., 2013; Wang, Wang, et al., Stroke, 2013).
Because of the involvement of TLR signals and IL-1 receptor family-mediated signals via IRAK4 in the case of pruritus and pain, for example cancer pain, post-operative pain, inflammation-induced and chronic pain, there may be assumed to be a therapeutic effect in the indications mentioned through the inhibition of IRAK4 (Wolf, Livshits, et al., Brain, Behavior, and Immunity, 2008; Kim, Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al., Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha, et al., European Journal of Pharmacology, 2012; Kwok, Hutchinson, et al., PLoS ONE, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; Han, Zhao, et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; Liu, Y. Zhang, et al., Cell Research, 2014).
This also applies to some oncological disorders. Particular lymphomas, for example ABC-DLBCL (activated B-cell diffuse large-cell B-cell lymphoma), mantle cell lymphoma and Waldenström's disease, and also chronic lymphatic leukaemia, melanoma and liver cell carcinoma, are characterized by mutations in MyD88 or changes in MyD88 activity which can be treated by an IRAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; (Liang, Chen, et al., Clinical Cancer Research, 2013). In addition, MyD88 plays an important role in ras-dependent tumours, and so IRAK4 inhibitors are also suitable for treatment thereof (Kfoury, A., K. L. Corf, et al., Journal of the National Cancer Institute, 2013).
Inflammatory disorders such as CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular) syndrome; FMF (familial mediterranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumour necrosis factor receptor 1-associated periodic syndrom), juvenile idiopathic arthritis, adult-onset Still's disease, Adamantiades-Behçet's disease, rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca and Sjögren syndrome are treated by blocking the IL-1 signal pathway; therefore here, too, an IRAK4 inhibitor is suitable for treatment of the diseases mentioned (Narayanan, Corrales, et al., Cornea, 2008; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of Immunology, 2011; Gul, Tugal-Tutkun, et al., Ann Rheum Dis, 2012; Pettersson, Annals of MedicinePetterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordstrom, Knight, et al., The Journal of Rheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013). The ligand of IL-33R, IL-33, is involved particularly in the pathogenesis of acute kidney failure, and so the inhibition of IRAK4 for prophylaxis and/or treatment is a suitable therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011). Components of the IL-1 receptor family are associated with myocardial infarction, different pulmonary disorders such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), and so prophylactic and/or therapeutic action is to be expected in the indications mentioned through the inhibition of IRAK4 (Kang, Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al., The Journal of Immunology, 2009; Abbate, Kontos, et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke, et al., European Respiratory Journal, 2011; Haenuki, Matsushita, et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li, et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013; Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013; Martínez-González, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Immunology, 2014).
The prior art discloses a multitude of IRAK4 inhibitors (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).
U.S. Pat. No. 8,293,923 and US20130274241 disclose IRAK4 inhibitors having a 3-substituted indazole structure. There is no description of 2-substituted indazoles.
WO2013/106254 and WO2011/153588 disclose 2,3-disubstituted indazole derivatives.
WO2007/091107 describes 2-substituted indazole derivatives for the treatment of Duchenne muscular dystrophy. The compounds disclosed do not have 6-hydroxyalkyl substitution.
WO2015/091426 describes indazoles, the alkyl group thereof substituted at position 2 by a carboxamide structure.
WO2015/104662 disloses indazole compounds of formula (I)
which are therapeutically useful as kinase inhibitor, particularly IRAK4 inhibitors, and pharmaceutically acceptable salts or stereoisomers thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme.
WO2016/083433, published after the priority date of the present application, describes novel substituted indazoles of the following formula
methods for the production thereof, use thereof alone or in combinations to treat and/or prevent diseases, and use thereof to produce drugs for treating and/or preventing diseases, in particular for treating and/or preventing endometriosis and endometriosis-associated pain and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria, and dyschezia, lymphomas, rheumatoid arthritis, spondyloarthritides (in particular psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver diseases, insulin resistance, tumor diseases, and psoriasis.
The novel IRAK4 inhibitor shall be especially suitable for treatment and for prevention of proliferative and inflammatory disorders characterized by an overreacting immune system. Particular mention should be made here of inflammatory skin disorders, cardiovascular disorders, lung disorders, eye disorders, autoimmune disorders, gynaecological disorders, especially endometriosis, and cancer.
A process was to be disclosed that would allow the production of indazole (I) on technical scale with special focus on the following requirements:                Scale-up/scalability of the manufacturing process        High regioselectivity in the N2-alkylation reaction        Avoidance of chromatographic separation and purification steps        Final processing via crystallization        Final adjustment of the polymorphic form using Class 3 solvents (in accordance with FDA guidelines)        
Remarkably, a process could be disclosed that meets all of the requirements mentioned above. This invention describes the preparation of compound (I) via a surprisingly highly selective alkylation on N2:

Preparations of N2-substituted indazoles have been previously described in the literature. These procedures, however, have considerable disadvantages rendering them unsuitable for technical scale. It is possible to selectively prepare N2-substituted indazoles via complex sequences of synthetic steps, which involve no direct alkylation step. These sequences, however, are long and tedious and involve considerable losses ultimately resulting in a low total yield. Therefore, synthetic routes which allow a direct preparation of N2-substituted indazoles from 1H-indazole precursors via direct and selective alkylation at N2 are most interesting. At the attempt of directly alkylating the 1H-indazole precursor of the general formula (II), generally a mixture made up of the N1- (IIIa) and N2-alkylated (III) regioisomers is obtained.

Indazole and its derivatives, a typical class of aromatic N-heterocycles, have sparked significant interest in synthetic and medicinal chemistry due to their diverse biological activities. Furthermore, diverse heterocyclic structures could be accessed from indazole-derived N-heterocyclic carbenes. Among indazoles, N1/N2-substituted indazoles are widely used as anticancer, anti-inflammatory, anti-HIV, and antimicrobial drugs. Generally, the synthesis of N2-substituted indazoles involves cyclization procedures from miscellaneous starting materials. Unfortunately, general methodologies remain scarce in the literature. Therein, only moderate yields were obtained.
With respect to the current state of technology, several publications are known and will be discussed in the following section. None of the published procedures feature reaction conditions that lead to a direct N2-selective alkylation using methyl vinyl sulfone as alkylating agent. There is either no conversion observed or the selectivity and yield are low. The problem of the prior art procedures consists in the use of relatively simple alkylating agents bearing no labile functional groups. These agents are mostly attached to the 1H-indazole via nucleophilic substitution of their halides, tosylates, triflates or mesylates. When more functionalized moieties are used, yield and selectivity decrease dramatically. In the following section, the reasons are presented why these prior art procedures are not applicable to the challenge at hand:                1. WO 2011/043479: The reactions are carried out in THF at reflux (see scheme 2). This does not work for the case at hand (methyl vinyl sulfone). The preparation of the corresponding triflate from e.g. the alcohol is not possible, as its decomposition occurs instantly. In addition, only a simple substrate with no functionality in the side-chain was used.        2. S. R. Baddam, N. U. Kumar, A. P. Reddy, R. Bandichhor, Tetrahedron Lett. 2013, 54, 1661: Only simple indazoles without functional groups were used in the reaction. Only methyl trichloroacetimidate was used as alkylating agent. Attempts to transfer acid-catalyzed conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed. This procedure cannot easily be scaled up.        3. Q. Tian, Z. Cheng, H. H. Yajima, S. J. Savage, K. L. Green, T. Humphries, M. E. Reynolds, S. Babu, F. Gosselin, D. Askin, Org. Process Res. Dev. 2013, 17, 97: The preparation of a THP-ether with preference for N2 of the indazole is presented. This reaction proceeds via a different mechanism and does not represent a general method, since the THP-ether product cannot be easily converted further. Furthermore, selective methods for protection of indazoles using p-methoxybenzyl derivatives under acidic conditions are presented. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.        4. D. J. Slade, N. F. Pelz, W. Bodnar, J. W. Lampe, P. S. Watson, J. Org. Chem. 2009, 74, 6331: THP-ether and PMB-protection using acidic conditions (PPTS: pyridinium para-toluenesulfonate), see scheme 2; attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.        5. M. Cheung, A. Boloor, J. A. Stafford, J. Org. Chem. 2003, 68, 4093: Highly reactive and highly carcinogenic Meerwein salts were used as alkylating agents (see scheme 2). This method only comprises simple non-functionalized ethyl and methyl Meerwein salts. The reaction proceeds in polar ethyl acetate at ambient temperature. These conditions could not be transferred to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone.        

                6. M.-H. Lin, H.-J. Liu, W.-C. Lin, C.-K. Kuo, T.-H. Chuang, Org. Biomol. Chem. 2015, 13, 11376: The procedure is N2-selective; however, it cannot be scaled up with Ga and Al metal being used in stoichiometric amounts. Under the described reaction conditions, Broensted acids are formed which react with the corresponding metals to give hydrogen gas. Only relatively simple substrates are used as alkylating agents (no sulfone group). When more functionalized substrates were used, a significant decrease in yield was observed. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.        7. G. Luo, L. Chen, G. Dubowchick, J. Org. Chem. 2006, 71, 5392: 2-(Trimethylsilyl)ethoxymethyl chloride (SEM-CI) in THF was used for substitution on N2 of indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed. The corresponding products described in this publication are ethers and are not related to our target molecule. The use of highly carcinogenic 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) as well as benzyloxymethyl chloride (BOM-Cl) does not represent a scalable option for obtaining the target compound.        8. A. E. Shumeiko, A. A. Afon'kin, N. G. Pazumova, M. L. Kostrikin, Russ. J. Org. Chem. 2006, 42, 294: Only very simple substrates were used in this method. No significant selectivity is reported. A slight preference for N1-alkylation at the indazole was observed.        9. G. A. Jaffari, A. J. Nunn, J. Chem. Soc. Perkin 1 1973, 2371: Very simple substrates and only methylation agents were used. A more complex substrate as e.g. a combination of formaldehyde with protonated methanol resulted in only N1-substituted product (ether).        10. V. G. Tsypin et al., Russ. J. Org. Chem. 2002, 38, 90: The reaction proceeds in sulfuric acid and chloroform. Only conversions of simple indazoles with adamanthyl alcohol as sole alkylating agent are described. These conditions could not be transferred to the selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone.        11. S. K. Jains et al. RSC Advances 2012, 2, 8929: This publication features an example of N-benzylation of indazoles with low selectivity towards N1-substitution. This KF-/alumina-catalyzed method cannot be used efficiently for the synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        12. L. Gavara et al. Tetrahedron 2011, 67, 1633: Only relatively simple substrates were used. The described acidic THP-ether formation and benzylation in refluxing THF are not applicable to our substrate. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        13. M. Chakrabarty et al. Tetrahedron 2008, 64, 6711: N2-alkylation was observed but N1-alkylated product was obtained preferentially. The described conditions of using aqueous sodium hydroxide and phase transfer catalyst in THF are not applicable to 2-substituted indazoles. Attempts to transfer these conditions to our system (methyl vinyl sulfone) failed.        14. M. T. Reddy et al. Der Pharma Chemica 2014, 6, 411: The reaction proceeds in the corresponding alkylating agent as solvent. Only the use of highly reactive ethyl bromoacetate as alkylating agent is reported. There are no data on the selectivity. These conditions are not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.        15. S. N. Haydar et al. J. Med. Chem. 2010, 53, 2521: Only simple non-functionalized alkyl groups are described (methyl, isopropyl, isobutyl). Cesium carbonate was used as base and the reaction resulted in a mixture of N1- and N2-alkylated products. These conditions are not applicable to compounds as 2-indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        16. Zh. V. Chirkova et al. Russ. J. Org. Chem. 2012, 48, 1557: In this method, relatively simple substrates are converted with potassium carbonate as base in DMF. Mixtures of N1- and N2-alkylated products are obtained. The conditions are not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        17. C. Marminon et al. Tetrahedron 2007, 63, 735: The ortho-substituent R in position 7 at the indazole directs the alkylation towards N2 via shielding N1 from electrophilic attacks. The conditions, sodium hydride as base in THF, are not applicable to a selective synthesis of N2-substituted indazoles as they preferentially result in alkylation at N1 in absence of a substituent in position 7 of the indazole. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        18. D. A. Nicewicz et al. Angew. Chem. Int. Ed. 2014, 53, 6198: Only simple substrates were used. This method describes a photochemical reaction that cannot easily be scaled up and is not applicable to a general, selective synthesis of N2-substituted indazoles Very specific styrene derivatives are used under radical reaction conditions. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        19. A. Togni et al. Angew. Chem. Int. Ed. 2011, 50, 1059: This publication solely describes a special type of substituent (hypervalent iodine as trifluoromethylation reagent in combination with acetonitrile). This special case is not applicable to a general, selective synthesis of N2-substituted indazoles.        20. L. Salerno et al. European J. Med. Chem. 2012, 49, 118: This publication describes the conversion of indazoles in an α-bromoketone melt. The reaction conditions cannot be transferred to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        21. K. W. Hunt, D. A. Moreno, N. Suiter, C. T. Clark, G. Kim, Org. Lett. 2009, 11, 5054: This publication essentially describes an N1-selective alkylation method with addition of different bases. Simple substrates were used. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        22. J. Yang et al. Synthesis 2016, 48, 48, 1139: This publication describes an N1-selective base-catalyzed aza-Michael reaction. No substitution at N2 was observed. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        23. P. R. Kym et al. J. Med. Chem. 2006, 49, 2339: Essentially N1-alkylations are described. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        24. A. J. Souers et al. J. Med. Chem. 2005, 48, 1318: This publication also describes the use of potassium carbonate as base. This method proceeds mainly with preference for substitution at N1 and is therefore not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        25. P. Bethanamudi et al. E-Journal of Chemistry 2012, 9, 1676: The use of ionic liquids along with potassium carbonate as base results in mixtures of N1- and N2-alkylated indazoles with low yields. The selectivity shows a tendency towards substitution at N1. The use of ionic liquid cannot be transferred to our system. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2-position of an indazole core structure via reaction with methyl vinyl sulfone failed.        26. S. Palit et al. Synthesis 2015, 3371: The reaction described herein is essentially non-selective with a slight preference of substitution at N1 of the indazole. Only simple, non-functionalized alkyl groups were used. Sodium hydride and similarly strong bases were used. Attempts to transfer these conditions to selective introduction of a methyl ethyl sulfone side chain at the N2 position of an indazole core structure via reaction with methyl vinyl sulfone failed.        